Thiourea compounds, compositions and methods and use

ABSTRACT

The compounds are dithiocarbamates and isothioureas which are histamine H 2  -antagonists. Two compounds of the invention are 2-(5-methyl-4-imidazolylmethylthio)ethyl N-methyldithiocarbamate and S-[2-(5-methyl-4-imidazolyl-methylthio)ethyl]-N-cyano-N&#39;-methylisothiourea.

This is a division of application Ser. No. 823,559, now U.S. Pat. No.4,120,966 Aug. 11, 1977 which is a division of application Ser. No.652,925, Jan. 27, 1976 now U.S. Pat. No. 4,056,621.

This invention relates to pharmacologically active compounds, topharmaceutical compositions containing these compounds and to methods ofblocking histamine H₂ -receptors by administering these compounds. Thecompounds of the invention can exist as acid addition salts but, forconvenience, reference will be made throughout this specification to theparent compound.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine is a typical example, anddiphenhydramine and chlorpheniramine are other examples, are mediatedthrough histamine H₁ -receptors (Ash and Schild, Brit. J. Pharmac.Chemother., 27, 427, (1966). However, other of the biological actions ofhistamine are not inhibited by "antihistamines" and actions of this typewhich are inhibited by a compound described by Black et al. (Nature,236, 385 (1972)) and called burimamide are mediated through receptorswhich are defined by Black et al. as histamine H₂ -receptors. Thushistamine H₂ -receptors may be defined as those histamine receptorswhich are not blocked by mepyramine but are blocked by burimamide.Compounds which block histamine H₂ -receptors are referred to ashistamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines". Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, for exampleas inhibitors of the effects of histamine on blood pressure. In thetreatment of certain conditions, for example inflammation and ininhibiting the actions of histamine on blood pressure, a combination ofhistamine H₁ -and H₂ -antagonists is useful.

The compounds of this invention are histamine H₂ -antagonists. Thesecompounds are represented by the following formula: ##STR1## wherein R₁represents a grouping of the structure shown in Formula 2:

    Het-- CH.sub.2 S(CH.sub.2).sub.2 --                        FORMULA 2

wherein Het is a nitrogen-containing 5 or 6 membered heterocylic ringsuch as imidazole, pyridine, thiazole, isothiazole, or thiadiazole,which ring is optionally substituted by lower alkyl, lower alkoxy orhalogen; R₂ is hydrogen, lower alkyl or the same as R₁ ; X is sulphur,═NH or ═NCN.

Throughout the present specification, by the term "lower alkyl" we meanan alkyl group containing from 1 to 4 carbon atoms, preferably methyl,and by the term "lower alkoxy" we mean an alkoxy group containing from 1to 4 carbon atoms, preferably methoxy. It will be understood that thestructure illustrated in Formula 1 is only one of severalrepresentations and that other tautomeric forms are also covered by thepresent invention. Hydrates, pharmaceutically acceptable salts, andhydrated pharmaceutically acceptable salts of compounds of Formula 1 arealso covered by the present invention.

Preferably Het is a 4-imidazolyl ring optionally substituted by halogenor lower alkyl, a 2-thiazolyl ring, a 3-isothiazolyl ring optionallysubstituted by halogen, or a 2-pyridyl ring optionally substituted bylower alkyl, halogen or lower alkoxy.

Particularly preferably Het is a 5-methyl-4-imidazolyl ring.

Examples of specific compounds falling within the scope of the presentinvention are 2-(5-methyl-4-imidazolylmethyl-thio)ethylN-methyldithiocarbamate,S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-N-cyano-N'-methylisothiourea,S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]isothiourea andS-(2-(5-methyl-4-imidazolylmethylthio)ethyl)dithiocarbamate.

Compounds of Formula 1 may be prepared by treating a compound of Formula3: ##STR2## wherein X and R₂ have the same significance as in Formula 1and A represents a lower alkyl group, with a mercaptan of Formula 4:

    R.sub.1 SH                                                 FORMULA 4

wherein R₁ is as defined in Formula 1. Preferably this reaction iscarried out in a solvent, such as pyridine, and at elevated temperaturese.g., 100° C.

The mercaptans of Formula 4 may be prepared by the reaction ofethanedithiol with a compound of Formula 5, in which Het has the samesignificance as in Formula 2, and Y represents chlorine or bromine.

    Het-- CH.sub.2 -- Y                                        FORMULA 5

Preferably this reaction is carried out in a solvent in the presence ofa base, such as with sodium ethoxide in dry ethanol.

Compounds of Formula 1 wherein X is sulphur may be preparedalternatively by the reaction of a mercaptan of Formula 4 with anisothiocyanate of formula R₂ NCS, R₂ being as defined in Formula 1.Preferably this reaction is carried out in a solvent such as pyridine.

The compounds of Formula 1 wherein X is sulphur and R₂ is hydrogen mayalso be prepared by treating a thiocyanate of formula R₁ SCN, R₁ beingas defined in Formula 1 with hydrogen sulphide. This reaction ispreferably carried out at low temperature in a solvent such as ethanol.The thiocyanates may conveniently be prepared by treating a compound ofthe formula R₁ Y, wherein R₁ is as defined in Formula 1 and Y ischlorine or bromine, with potassium thiocyanate.

Compounds of Formula 1 wherein X is ═NH may be prepared alternatively bytreating a compound of Formula 6: ##STR3## wherein R₂ is as defined inFormula 1, with a compound of Formula R₁ Y where R₁ is as defined inFormula 1 and Y is chlorine or bromine. The compounds of formula R₁ Ymay be prepared from the corresponding alcohols of formula R₁ OH bystandard techniques, e.g., the chlorides may be prepared from thecorresponding alcohols by treatment with thionyl chloride.

The alcohols of formula R₁ OH may be prepared by the reaction ofmercaptoethanol with a compound of formula HetCH.sub. 2 Y, in which Hethas the same significance as in Formula 2 and Y represents chlorine orbromine. Preferably this reaction is carried out in a solvent in thepresence of a base, such as with sodium ethoxide in dry ethanol.

The compounds of Formula 1 block histamine H₂ -receptors, that is theyinhibit the biological actions of histamine which are not inhibited by"antihistamines" such as mepyramine but are inhibited by burimamide. Forexample, the compounds of this invention have been found to inhibithistamine-stimulated secretion of gastric acid from the lumen-perfusedstomachs of rats anaesthetized with urethane, at doses of from 0.5 to256 micromoles per kilogram intravenously. This procedure is referred toin the above mentioned paper of Ash and Schild. The activity of thesecompounds as histamine H₂ -antagonists is also demonstrated by theirability to inhibit other actions of histamine which, according to theabove mentioned paper of Ash and Schild, are not mediated by histamineH₁ -receptors. For example, they inhibit the actions of histamine on theisolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastricacid and also that stimulated by pentagastrin or by food.

In addition, the compounds of this invention show anti-inflammatoryactivity in conventional tests such as the rat paw oedema test, wherethe oedema is induced by an irritant, the rat paw volume is reduced bysubcutaneous injection of doses of about 500 micromoles/kg of a compoundof Formula 1.

In a conventional test, such as the measurement of blood pressure in theanaesthetised cat, the action of the compounds of this invention ininhibiting the vasodilator action of histamine can also be demonstrated.The level of activity of the compounds of this invention is illustratedby the effective dose producing 50% inhibition of gastric acid secretionin the anaesthetized rat and the dose producing 50% inhibition ofhistamine-induced tachycardia in the isolated guinea pig atrium.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in associated with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula 1 bystandard procedures, for example by treating the base with an acid in alower alkanol or by the use of ion exchange resins to form the requiredsalt either directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula 1 or a pharmaceutically acceptable acid additionsalt thereof and methods of blocking histamine H₂ -receptors whichcomprise administering a compound of Formula 1 or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid contained for example in an ampoule,or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount of block histamine H₂ -receptors. The route of administration maybe oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administered one to six timesper day. The daily dosage regimen will preferably be from about 150 mgto about 1500 mg.

Advantageously the composition will be made up in a dosage formappropriate to the desired mode of administration, for example as atablet, capsule, injectable solution or as a cream or ointment fortopical application.

The invention is illustrated and in no way limited by the followingexamples wherein all temperatures are given in degrees Centigrade:

EXAMPLE 1 2-(5-Methyl-4-imidazolylmethylthio)ethylN-methyl-dithiocarbamate dithiocarbamate

(a) Sodium (5.2 g) was added, with stirring under nitrogen, to dryethanol (150 ml). After the sodium had dissolved ethanedithiol (40 ml)was introduced and to this mixture was added4-methyl-5-chloromethylimidazole hydrochloride (15 g), as a solid, overa period of 1.5 hours at room temperature. The mixture was then stirredfor a further 1 hour at room temperature. After this time a saturatedsolution of hydrogen chloride in ethanol was added until the mixture wasacidic. The temperature was then raised and the ethanol distilled offunder nitrogen. The residue was taken up in water and continuouslyextracted with ether to remove the excess etanedithiol. The aqueousfraction was then evaporated to dryness and the residue extracted withhot isopropanol. Reducing the volume of the extract and cooling afforded2-(5-methyl-4-imidazolyl-methylthio)ethanethiol hydrochloride as a whitesolid which was not purified further.

(b) A solution of sodium carbonate was added to s solution of2-(5-methyl-4-imidazolylmethylthio)ethanethiol hydrochloride (2.8 g) inwater (50 ml) to pH9 and the mixture extracted with ethyl acetate. Afterdrying (MgSO₄), the extract was evaporated to dryness and the residuetaken up in pyridine (25 ml). To this solution was addedmethylisothiocyanate(1.1 g) and the mixture stirred at room temperaturefor 1 hour. After this time the mixture was evaporated to give the crudetitle product. This residue was taken up in ethanol and a saturatedsolution of hydrogen chloride in ethanol added until the mixture wasacidic. Addition of ether to this solution afforded a white solid whichafter repeated recrystallisation from ethanol/ether gave2-(5-methyl-4-imidazolylmethylthio)ethyl-N-methyldithiocarbamatehydrochloride, m.p. 171°-172°.

(Found: C, 36.5; H, 5.3; N, 14.1; S, 31.9; Cl, 12.2; C₉ H₁₅ N₃ S₃.HClrequires; C, 36.3; H, 5.4; N, 14.1; S, 32.3; Cl, 11.9%)

This hydrochloride may be treated with aqueous sodium carbonate and themixture extracted with chloroform and the chloroform extracts evaporatedto give the free base.

EXAMPLE 2S-[2-(5-Methyl-4-imidazolylmethylthi0)ethyl]-N-cyano-N'-methylisothiourea

2-(5-Methyl-4-imidazolylmethylthio)ethanethiol (4.0 g) (prepared fromthe hydrochloride as in Example 1(b) and N-cyano-N',S-dimethylisothiourea (4.0 g) were heated together under nitrogen inpyridine (100 ml) at 100° for 20 hours. After this time the mixture wasevaporated to dryness to give the crude title product. This residuetaken up in water acidified to pH2 with concentrated hydrochloric acid.After extracting with ethyl acetate the volume of the aqueous fractionwas reduced and on cooling gaveS-[2-(5-methyl-4-imidazolylmethylthio)-ethyl]-N-cyano-N'-methylisothioureahydrochloride, m.p. 225°.

(Found: C, 39.3; H, 5.4; N, 23.1; S, 21.2; Cl, 11.7; C₁₀ H₁₅ N₅ S₂. HClrequires; C, 39.3; H, 5.2; N, 23.0; S, 21.0; Cl, 11.6%).

This hydrochloride may be treated with aqueous sodium carbonate and themixture extracted with chloroform and the chloroform extracts evaporatedto give the free base.

EXAMPLE 3 S-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]isothiourea

(a) Sodium (3.0 g) was added, with stirring under nitrogen, to dryethanol (75 ml). After the sodium had dissolved mercaptoethanol (9.0 ml)was introduced and to this mixture was added4-methyl-5-chloromethylimidazole hydrochloride (10 g), as a solid, overa period of 1.5 hours at room temperature. The mixture was then stirredfor a further 1 hour at room temperature. After this time the reactionwas warmed and the ethanol distilled off at reduced pressure. Theresidue was taken up in water, acidified with concentrated hydrochloricacid, and continuously extracted with ether to remove the excessmercaptoethanol. The aqueous fraction was then basified using solidsodium carbonate and continuously extracted with ethyl acetate. To theextract was added a further volume of ethyl acetate and the whole warmedto re-dissolve the crude product which had deposited. After drying(MgSO₄) and reducing the volume, crystallisation from this solutionbelow 40° and cooling to -15° afforded2-(5-methyl-4-imidazolylmethylthio)ethanol, m.p. 74°-76°.

(Found: C, 49.1; H, 6.8; N, 16.2: C₇ H₁₂ N₂ O S requires: C, 48.8; H,7.0; N, 16.3%).

(b) 2-(5-Methyl-4-imidazolylmethylthio)ethanol (0.34 g, 2 mmol) andthionyl chloride (0.238 g, 2 mmol) were heated together, with stirring,at reflux temperature in chloroform (10 ml) for one hour, giving a greysolution and a green oil. A second equivalent of thionyl chloride (0.238g) was added at reflux temperature and immediately the oil went intosolution and a solid started to crystallise. After a further 15 minutesat reflux temperature the mixture was cooled and the solid collected(0.395 g). Recrystallisation from acetonitrile gave1-chloro-2-(5-methyl-4-imidazolylmethylthio)ethane hydrochloride, m.p.163°-165°, (0.29 g).

(Found: C, 37.1; H, 5.2; N, 12.6; S, 14.1; Cl, 31.2: C₇ H₁₁ Cl N₂ Srequires: C, 37.0; H, 5.3; N, 12.3; S, 14.1: Cl, 31.2%).

(c) 1-Chloro-2-(5-methyl-4-imidazolylmethylthio)ethane hydrochloride(3.9 g, 17 mmol) and thiourea (1.30 g, 17 mmol) were heated together atreflux temperature for 48 hours in ethanol (50 ml). After cooling theethanol was evaporated to give the crude title product as an oil. Thisoil was converted to the sulphate salt by dissolution in water (220 ml)and passage down an ion-exchange column. The water was evaporated andthe residual oil triturated with boiling methanol to give a white solid(4.33 g). Crystallisation of this solid from aqueous methanol gaveS-[2-(5-methyl-4-imidazolylmethylthio)ethyl]isothiouronium sulphate(3.70 g), m.p. 217°-220°.

(Found: C, 29.4; H, 5.1; N, 17.1; S, 29.0; C₈ H₁₄ N₄ S₂. H₂ SO₄.requires: C, 29.3; H, 4.9; N, 17.1; S, 29.3%).

This sulphate may be treated with aqueous sodium carbonate and themixture extracted with chloroform and the chloroform extracts evaporatedto give the free base.

EXAMPLE 4 S-[2-(5-Methyl-4-imidazolylmethylthio)ethyl]dithiocarbamate

(i) 1-Chloro-2(5-methyl-4-imidazolylmethylthio)ethane hydrochloride (2.1g) and potassium thiocyanate (0.97 g) were heated together under refluxin ethanol (50 ml) for 3 days. The mixture was evaporated to dryness andthe residue was taken up in water, basified with sodium carbonate andextracted with chloroform. The chloroform extracts were dried (MgSO₄)and evaporated to a residue which was recrystallised from acetonitrileto give 2-(5-methyl-4-imidazolylmethylthio)ethylthiocyanate m.p.101°-103°. (Found: C, 45.3; H, 5.3; N, 19.5; S, 29.3. C₈ H₁₁ N₃ S₂requires: C, 45.0; H, 5.2; N, 19.7; S, 30.1%).

(ii) Hydrogen sulphide was passed for 1 hour at a pressure of 15 cm.Hgabove atmospheric into a solution of2-(5-methyl-4-imidazolylmethylthio)ethyl thiocyanate (2.0 g) in ethanol(20 ml) at -15°. Ethanolic hydrogen chloride was added followed byether. The crude solid was taken up in water, treated with concentratedaqueous sodium carbonate and the mixture was extracted with chloroform.The chloroform extracts were dried and evaporated and the residue waspurified by column chromatography (silica gel/5% methanol in chloroform)to give S-[2-(5-methyl-4-imidazolylmethylthio)ethyl]dithiocarbamate.Reconversion to the hydrochloride by treatment with ethanolic hydrogenchloride and recrystallisation from ethanol affordedS-[2-(5-methyl-4-imidazolylmethylthio)ethyl]dithiocarbamatehydrochloride, m.p. 191°-193°.

(Found: C, 34.1; H, 5.0; N, 14.9; S, 32.2; Cl, 12.3: C₈ H₁₃ N₃ S₃.HClrequires: C, 33.8; H, 5.0; N, 14.8; S, 33.9; Cl, 12.5%)

EXAMPLE 5N,S-bis[2-(5-Methyl-4-imidazolylmethylthio)ethyl]-N'-cyanoisothiourea

2-(5-Methyl-4-imidazolylmethylthio)ethanethiol andN-cyano-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]-S-methylisothioureaare heated together under nitrogen in pyridine at 100° for 20 hours andthe mixture evaporated to give the crude title product. This residue istreated with hydrochloric acid to yield the hydrochloride of the titleproduct.

EXAMPLE 6 N,S-bis[2-(5-Methyl-4-imidazolylmethylthio)ethyl]isothiourea

1-Chloro-2-(5-methyl-4-imidazolylmethylthio)ethane andN-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea are heated togetherat reflux temperature in ethanol, and the mixture is evaporated and theresidue purified to give the title compound, which may be converted intoa suitable salt by ion-exchange chromatography.

EXAMPLE 7

Substitution of:

(a) 4-(chloromethyl)imidazole

(b) 2-(chloromethyl)thiazole

(c) 3-(bromomethyl)isothiazole

(d) 4-bromo-3-(bromomethyl)isothiazole

(e) 2-(chloromethyl)-3-methylpyridine

or salts thereof for 4-chloromethyl-5-methylimidazole hydrochloride inthe procedure of Example 1 leads to the production of:

(a) 2-(4-imidazolylmethylthio)ethyl N-methyldithiocarbamate

(b) 2-(2-thiazolylmethylthio)ethyl N-methyldithiocarbamate

(c) 2-(3-isothiazolylmethylthio)ethyl N-methyldithiocarbamate

(d) 2-(4-bromo-3-isothiazolylmethylthio)ethyl N-methyldithiocarbamate

(e) 2-(3-methyl-2-pyridylmethylthio)ethyl N-methyldithiocarbamate

and conversion of the above-mentioned halomethyl derivatives to thecorresponding methylthioethylthiols by the procedure described inExample 1 followed by treatment with N-cyano-N',S-dimethylisothioureaaccording to the procedure of Example 2 leads to the production of:

(a) S-[2-(4-imidazolylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

(b) S-[2-(2-thiazolylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

(c) S-[2-(3-isothiazolylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

(d)S-[2-(4-bromo-3-isothiazolylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

(e)S-[2-(3-methyl-2-pyridylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

EXAMPLE 8

(a)

(i) 3-Hydroxy-2-hydroxymethylpyridine (4.4 g) was added to a solution ofsodium (0.81 g) in methanol (50 ml). The solvent was evaporated off,treated with toluene, reevaporated and taken up in dimethylsulphoxide(88 ml) to which was added methyl iodide (5.0 g) in dimethylsulphoxide(12 ml) while the solution was stirred for 30 minutes at 18°. Afterstirring overnight, the solvent was removed and the residue waspartitioned between chloroform and water. The chloroform extract wasevaporated and a solution of the residue in ethanol was treated withethanolic hydrogen chloride to yield 2-hydroxymethyl-3-methoxypyridinehydrochloride (3.0 g) m.p. 208° dec. 2-Hydroxymethyl-3-methoxypyridine(4.2 g) was dissolved in chloroform (60 ml) and to the stirred solutionwas added thionyl chloride (6 ml). After stirring for 90 minutes andevaporation of the solvent, the residue was recrystallised fromethanol/ether to give 2-chloromethyl-3-methoxypyridine hydrochloride(5.1 g), m.p. 171.5°-172.5°.

(ii) A solution of sodium nitrite (2.38 g) in water (10 ml) was addeddropwise to a mixture of 3-amino-2-hydroxymethylpyridine (4.8 g),aqueous hydrochloric acid (48%, 10 ml) and water (5 ml) stirred at0°-5°. This solution was added to a hot solution of cuprous chloride(2.5 g) in conc. hydrochloric acid and the mixture was heated on asteam-bath for 0.5 hours, diluted with water and saturated with hydrogensulphide. The mixture was filtered, concentrated and extracted withchloroform and the chloroform extract was evaporated to give3-chloro-2-hydroxymethylpyridine (3.7 g) m.p. 42°-44° (from n-pentane).

(iii) 3-Chloro-2-hydroxymethylpyridine, 3-bromo-2-hydroxymethylpyridineand 4-bromo-5-hydroxymethylimidazole may be converted into3-chloro-2-chloromethylpyridine, 3-bromo-2-chloromethylpyridine and4-bromo-5-chloromethylimidazole by treatment with thionyl chloride asdescribed above.

(b) Substitution of:

(a) 2-Chloromethyl-3-methoxypyridine

(b) 3-Chloro-2-chloromethylpyridine

(c) 3-Bromo-2-chloromethylpyridine

(d) 4-Bromo-5-chloromethylimidazole

or salts thereof for 4-chloromethyl-5-methylimidazole hydrochloride inthe procedure of Example 1 leads to the production of:

(a) 2(3-methoxy-2-pyridylmethylthio)ethyl N-methyldithiocarbamate

(b) 2-(3-chloro-2-pyridylmethylthio)ethyl N-methyldithiocarbamate

(c) 2-(3-bromo-2-pyridylmethylthio)ethyl N-methyldithiocarbamate

(d) 2-(5-bromo-4-imidazolylmethylthio)ethyl N-methyldithiocarbamate

and conversion of the above-mentioned chloromethyl derivatives to thecorresponding methylthioethylthiols by the procedure described inExample 1 followed by treatment with N-cyano-N',S-dimethylisothioureaaccording to the procedure of Example 2 leads to the production of:

(a)S-[2-(3-methoxy-2-pyridylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

(b)S-[2-(3-chloro-2-pyridylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

(c)S-[2-(3-bromo-2-pyridylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

(d)S-[2-(5-bromo-4-imidazolylmethylthio)ethyl]-N-cyano-N'-methylisothiourea

EXAMPLE 9

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        S-[2-(5-methyl-4-imidazolylmethyl-                                            thio)ethyl]-N-cyano-N'-methylisothio-                                         urea hydrochloride       150    mg.                                           Sucrose                  75     mg.                                           Starch                   25     mg.                                           Talc                     5      mg.                                           Stearic Acid             2      mg.                                           ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 10

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        S-[2-(5-methyl-4-imidazolylmethyl-                                            thio)ethyl]-N-cyano-N'-methylisothio-                                         urea hydrochloride       200 mg.                                              Lactose                  100 mg.                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 11 2-(5-Methyl-4-imidazolylmethylthio)ethylN-[2-(5-methyl-4-imidazolylmethylthio)ethyldithiocarbamate.

(i) A solution of 2((5-methyl-4-imidazolyl)methylthio)ethylamine (3.42g, 0.02 mol) in dry pyridine (15 ml) was slowly added under dry nitrogento a stirred solution of dicyclohexylcarbodiimide (4.12 g, 0.02 mol) andcarbon disulphide (20 ml) in dry pyridine (10 ml) at -10°. After beingstirred for 4 hours at -10° then 18 hours at room temperature the cooled(0°) reaction mixture was filtered from dicyclohexylthiourea which waswashed with ether. The combined filtrate and washings were evaporatedunder reduced pressure to dryness, traces of pyridine being removed byazeotropic distillation with water (50 ml) then isopropanol (50 ml). Theresidue was heated with acetonitrile (25 ml) and cooled to 0°, filteredand the filtrate was heated with excess ethanolic hydrogen chloride,then evaporated again to dryness. Recrystallisation of the residue fromacetonitrile gave 5-methyl-4-(2-isothiocyanatoethylthiomethyl)imidazolehydrochloride (2.5 g) m.p. 150°-151°.

(Found: C, 38.6; H, 5.1; N, 17.0; S, 25.5; Cl; 14.1; C₈ H₁₁ N₃ S₂. HClrequires; C, 38.5; H, 4.8; N, 16.8; S, 25.7; Cl, 14.2%)

(ii) 5-Methyl-4-(2-isothiocyanatoethylthiomethyl)imidazole hydrochloridemay be treated with one equivalent of triethylamine and2-(5-methyl-4-imidazolylmethylthio)ethanethiol according to the generalprocedure of Example 1(b) to give the title product.

EXAMPLE 12S-[2-((1,2,5-Thiadiazol-3-yl)methylthio)ethyl]-N-cyano-N'-methylisothiourea

(1) A mixture of N-bromosuccinimide (18.0 g), 4-methyl-1,2,5-thiadiazole(10.0 g), benzoyl peroxide (0.1 g) and carbon tetrachloride (250 mls)was illuminated by a 350 watt bulb and boiled under reflux for 5 hours.The mixture was left overnight at room temperature, filtered, and thefiltrate was evaporated and distilled to give3-bromomethyl-1,2,5-thiadiazole (6.4 g) b.p. 98°-115°/16 mm. Thismaterial may be purified by preparative gas-liquid chromatography.

(2) Conversion of 3-bromomethyl-1,2,5-thiadiazole into2-((1,2,5-thiadiazol-3-yl)methylthio)ethane thiol by the procedure ofExample 1 and treatment of this product withN-cyano-N',S-dimethylisothiourea according to the procedure of Example 2leads to the production of the title compound.

What is claimed is:
 1. A compound of the formula: ##STR4## wherein R₁represents a grouping of the structure

    Het-- CH.sub.2 S(CH.sub.2).sub.2 --

wherein Het is a thiazole, isothiazole, or thiadiazole ring, which ringis optionally monosubstituted or disubstituted by lower alkyl, loweralkoxy or halogen R₂ is hydrogen, lower alkyl or the same as R₁ ; X issulphur, ═NH or ═NCN; or a hydrate or pharmaceutically acceptable acidaddition salt or hydrated salt thereof.
 2. A compound of claim 1 whereinHet is a 2-thiazolyl ring or a 3-isothiazolyl ring optionallysubstituted by halogen, or a hydrate or pharmaceutically acceptable acidaddition salt or hydrated salt thereof.
 3. A pharmaceutical compositionto block histamine H₂ receptors comprising in an effective amount toblock said receptors a compound of claim 1 in combination with apharmaceutically acceptable diluent or carrier.
 4. A method of blockinghistamine H₂ -receptors which comprises administering to an animal in aneffective amount to block said receptors a compound of claim 1.